2010 Fiscal Year Final Research Report
The transcription factor AP-1 as a molecular target in sepsis therapy
| Project/Area Number |
20590250
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | University of Toyama |
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Principal Investigator |
HATTORI Yuichi University of Toyama, 医学薬学研究部(医学), 教授 (50156361)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOO Hiroki 富山大学, 医学薬学研究部(医学), 准教授 (30332894)
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| Co-Investigator(Renkei-kenkyūsha) |
TAKANO Yasuo , 神奈川県立がんセンター臨床研究所, 所長 (60142022)
MATSUDA Naoyuki 名古屋大学, 医学研究科, 教授 (50332466)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 炎症・免疫 / 敗血症 / 転写因子 / アポトーシス |
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| Research Abstract |
Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice (8-12 wk of age). The DNA binding activity of AP-1, as assessed by electrophoretic mobility shift assay, was time-dependently increased in lung tissues from mice after the onset of CLP-induced sepsis. This increase was effectively eliminated by in vivo transfection of AP-1 decoy oligonucleotides (ODNs). Sepsis induction significantly increased surface expression of death receptors, such as TNF-R1, Fas, DR4, and DR5, in lung and aortic tissues after sepsis. Furthermore, the gene and protein levels of FADD, which recruits procaspase-8 into the death-inducing signaling complex, were increased after sepsis induction. These sepsis-induced changes were eliminated by systemic application of AP-1 decoy ODNs. TUNEL assays revealed that the significant appearance of cell apoptosis in lung and aortic tissue sections from septic mice was prevented by systemic treatment with AP-1 decoy ODNs. When endotoxic shock was induced by an intravenous injection of 10mg/kg lipopolysaccharide (LPS) in mice, expression levels of inflammatory molecules, including IL-1R, IL-6R, HMGB-1, and gp130, were highly increased, which was significantly inhibited by AP-1 decoy ODN treatment. All animals which received LPS died within 48h, and the animals that were treated with AP-1 decoy ODNs after LPS exhibited a striking improvement of survival. Our results suggest that AP-1 decoy ODN therapy represent an effective strategy in the treatment of sepsis. In addition, systemic administration of siRNA targeting FADD, which was found to be transactivated by AP-1, prevented the development of acute lung injury in CLP mice, and improved their survival. These findings indicate the potential usefulness of FADD siRNA for gene therapy of the septic syndrome.
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Research Products
(9 results)
